Purified botanical extracts have long been a source of new and useful pharmaceutical. Plant root extracts from the family Annonaceae have been reported in the literature to have potent cytotoxic and antimicrobial activity. Plants from the family annonaceae, genus Uvaria, have been found to contain compounds such as acetogenins useful as pesticides, and recently as anticarcinogenic agents.
U.S. Pat. No. 5,229,419, discloses such chemo-therapeutically active acetogenins. That invention relates to two acetogenin compounds isolated in substantially pure form from a plant in the Annonaceae family, Annona bullata Rich. the two compounds, bullatacin and bullatacinone, were found to exhibit antitumor and pesticidal activity and were characterized as being new members of an unusual class of compounds. The compounds are composed of tetrahydrofuran rings having two adjacent hydroxyl groups.
The starting material for obtaining the purified extracts is the root bark of the Annona bullata Rich. plant. Obtaining the purified extracts is performed by standard sterilization and purification processes.
U.S. Pat. No. 4,855,319, discloses an Annonaceous acetogenin for the control of pests. In that reference, a new acetogenin called asimicin was extracted from the root bark of a plant from the Annonaceae family. The particular extract was isolated from the plant Asimina triloba, also known as the paw paw tree. However, it is noted in that reference that the most potent form of the Asimina triloba extract is taken from the bark of the plant, not the root. The extract appears to be a tetrahydrofuranoid fatty acid lactone having variable side chains, however the disclosure is directed to the substantially pure compound, Asimicin.
U.S. Pat. No. 4,721,727, also discloses a purified Annonaceous extract which uses tetrahydrofuranoid acetogenins for controlling pests. That reference is also directed only to use of the compound Asimicin.
Other reported literature has shown that the compound, Uvaricin, taken from the purified root extracts of Uvaria acuminata, another Annonaceous plant, demonstrated an in vitro activity against P-388 lymphocytic leukemia in mice. [Jolad, et al., J. Org. Chem., 47:3 151-3153 (1982)]
Another extract, Uvaratin, also from Uvaria acuminata, was also shown to have anti-tumor activity. [Cole, et al., J. Org. Chem 41 (10)pp. 1852-1855, (1976)].
In fact, the literature contains numerous reports that plant extracts from the Annonaceae family have been investigated for their medicinal and toxicological effects. In one pharmacological screening, substantial antibacterial, antifungal, and anthelminthic activities were observed using extracts of the root barks of Uvaria Narum Wall, and Uvaria Hookeri king. [Padmaja et al., J. Ethnopharmacol (IRELAND), 40(3) pp. 181-186 (December, 1993)].
In another study, species from Uvaria originating from Tanzanian plants were tested for their in vitro activity against the multi-drug resistant K 1 strain of plasmodium falciparum, the causative agent for the disease malaria. In this study, root extracts from the stem and root barks, of Uvaria lucida and Uvaria sp. (pande), were reported as having anti-malarial activity. Among the compounds isolated in this study were Uvaretin, Diuveretin, and 8',9'-dihydroxy-3-farnesylindole as the most active compounds. The particular Uvaria species consisted of nine varieties from Tanzania and included: U. dependens, U. faulknerae, U. kirkii, U. leptocaldon, U. lucida, Uvaria sp. (Pande), U. scheffieri, and U. tanzaniae. [Nkunya et al., Planta Med, 57 (4) pp. 341-3, (1991)].
Yet another species, Uvaria chamae, has also been reported to have anti-microbial activities. In that study, cytotoxic C-benzylated flavonoids exhibited anti-microbial inhibition which compared favorably to that of streptomycin sulfate, an inhibitor of protein synthesis. [Hufford, et al., J. Art., 41 (2) pp. 156-60, (1978)]. However, compounds taken from the roots of Uvaria chamai has also been implicated as a causative agent for liver cancer. Two separate studies out of sub-Saharan Africa have shown that the active compound in Uvaria chamaii, chamuvaritin, has shown that it has mutagenic effects. One of the studies also showed that sub-Saharan Africa is a high incidence area for hepatocellular carcinoma. Although the disease is multi-factorial in etiology, including a combination of causative agents such as Hepatitis B Virus, and chemical carcinogens, the compounds contained in the medicinal plants were implicated as potential sources of causative agents for liver cancer. [Uwaifo, et al., IARC Sci. Publ., 63 pp. 59-88 (1984). (Uwaifo, et al., Cancer Lett, 8 (1) pp. 87-92 (1972)].
In addition to the cytotoxic, antitumor, and antimicrobial activities of plant extracts from the Annonaceae family, other root bark extracts are reported in the literature as having medicinal purposes. One compound, 15-desacetylundulatone, a quassinoid, was found active against P-388 mouse lymphocytic leukemia cells and Colon-38 adenocarcinoma. [Lumonadio et al., J. Ethnopharmacol., 31 (1) pp. 59-65, (SWITZERLAND) (January, 1991 )].
Prior literature has also reported root bark extracts capable of anti-viral activity. An anti-Herpes virus compound was purified from the root bark extract of the citrus plant (Rutaceae). [Yamamoto et al., J. Antiviral Res., 12(1) pp. 21-36, (NETHERLANDS) (August, 1989)]. In that study, the compound exhibited potent activity against Herpes Simplex Virus Type 1 (HSV-1) and Herpes Simplex Virus Type 2 (HSV-2) at low concentrations relative to their cytotoxicity. Additionally, the compound was also shown to suppress Cytomegalovirus (CMV), another member of the Herpes virus family.
Although the exact mechanism of action of root bark compounds taken from the Annonaceae family is not known, two recent articles may provide some insight. Annonaceous acetogenins, natural products from the plants described above, were shown to be very potent inhibitors of the NADH-Ubiquinone Reductase (Complex I) activity of mammalian mitochondria, and exhibit a high potential for interfering with the production of energy within mammalian cells. The acetogenins, Rolliniastatin-1 and Rolliniastatin-2, were compared against classical inhibitors of Complex I and were shown to be more powerful in terms of both their inhibitory constant and the protein dependence of their titer in bovine submitochondrial particles. Although the above results only apply to Rolliniastatin-1 and Rolliniastatin-2, Squamocin and Otivarin also showed an inhibitory constant lower than that of the classical inhibitor. [Degli, et al., Bio. Chem. J, 301 (Pt. 1 ) pp. 161-7, (1994)].
Another potential mechanism of action may be similar to that of Annonaceous alkaloids. These compounds show a selective toxicity against DNA repair and recombination-deficient mutants of the yeast. Saccharomyces cerevesie. [Harrigan, et al., J. Nat. Prod., 57 (1) pp. 68-73, ( 1994)]. However, Herpes viruses have large genomes consisting of double-stranded DNA and dedicated viral machinery for DNA synthesis. Thus, the inherent structure double-stranded DNA viruses, like those of the Herpes virus family, will provide treatments which may only be effective against viruses of the same family.
However, there is no reference in the literature reporting that the use of plant root extracts or compounds generated from the family Annonaceae would be efficacious in an anti-viral capacity. Further, there is no reference in the prior art that a plant extract from the Uvaria genus of the Annonaceae family may be useful in an antiviral capacity. As an antineoplastic agent, or as a treatment for diseases caused by immunodeficiency.